Hutchinson-Gilford progeria syndrome: Rejuvenating old drugs to fight accelerated ageing

Guilbert, Solenn M.; Cardoso, Déborah; Lévy, Nicolas; Muchir, Antoine; Nissan, Xavier

doi:10.1016/j.ymeth.2020.04.005

Cited by 25 publications

(23 citation statements)

References 115 publications

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“…Understanding molecular mechanisms and pathological features of progerin is essential for developing clinical treatment for patients with HGPS. Over the past decade, active progress in HGPS research has led to an increasing number of treatment strategies [31][32][33][34][35][36] . Nevertheless, most of previous studies had insufficient preclinical data for transposition to patients with HGPS.…”

Section: Discussionmentioning

confidence: 99%

Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome

et al. 2021

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Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient’s cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of LmnaG609G/G609G mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of LmnaG609G/+ mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of LmnaG609G/+ mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in LmnaG609G/+ mouse. These results indicate that progerinin is a strong drug candidate for HGPS.

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Section: Discussionmentioning

confidence: 99%

Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome

et al. 2021

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“…However, the gene editing can create unintended, or 'off-target' effects [22]. Moreover, inducing progerin clearance through activating autophagy with mTOR inhibitors and reducing progerin downstream effects can be potential therapies for patients with HGPS [23,24]. These therapies show some favorable effects in HGPS models but also caused side effects with toxicity [25,26].…”

Section: Discussionmentioning

confidence: 99%

Development of a new drug for progeria syndrome; Past, Present and Future

Kang¹,

Kim²,

Park³

2020

Arch Gerontol Geriatr Res

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Direct interaction between lamin A/C and progerinSeveral reports dealing with proteomic studies and 2-hybrid approaches have identifi ed lamin A/C as a progerin-binding protein [12,13]. Knowledge of these studies presupposed that interaction of progerin with lamin A/C would contribute to the development of the senescence features of HGPS. In 2016, we reported that C-terminal region of progerin strongly interact with lamin A and C but not lamin B1 [14]. The above study

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“…As MSCs transplantation can ameliorate aging associated disorders and extend lifespan [43], it is plausible MSCs will serve as a novel therapeutic strategy for HGPS in addition to other approaches like targeting lamin A post translational process, modulating progeria or prelamin A level, activation of autophagy and reprogramming [44][45][46]. To fulfil this purpose and avoid potential undesired immune response, we generated genetically rectified autologous MSCs.…”

Section: Correction Of Pathogenic Mutation In Hgps Cells By a Crispr/...mentioning

confidence: 99%

Rapid and robust derivation of mesenchymal stem cells from human pluripotent stem cells via temporal induction of neuralized ectoderm

Jin

et al. 2022

Cell Biosci

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Background Mesenchymal stem cells (MSCs) are emerging as the mainstay of regenerative medicine because of their ability to differentiate into multiple cell lineages. The infinite proliferative potential of human pluripotent stem cells (PSCs) grants an unlimited supply of MSCs. Despite their great potential in therapeutic applications, several drawbacks have hindered its clinical translation, including limited number of replication, compromised potential and altered function in late passages. The aim of this study is to establish an efficient method for the production of MSCs from pluripotent stem cells for potential clinical application in rare human disease Hutchinson-Gilford progeria syndrome. Results We established a robust method allowing rapid derivation of MSCs from both human iPSCs and ESCs via a temporal induction of neural ectoderm in chemically defined media. The iPSC- and ESC-derived MSCs satisfy the standard criteria of surface markers. They exhibited a high tri-lineage differentiation potential with over 90% transcriptional similarity to the primary MSCs derived from bone marrow. To evaluate the potential application of this method in disease modeling, MSCs were generated from iPSCs derived from a patient with Hutchinson-Gilford progeria syndrome (HGPS-MSCs) and from mutation-rectified HGPS-iPSCs (cHGPS-MSCs). HGPS-MSCs manifested accelerated senescence whereas mutation rectification rescued cellular senescence in HGPS-MSCs. Conclusions The robust method of MSC derivation from ESCs and iPSCs provides an efficient approach to rapidly generate sufficient MSCs for in vitro disease modeling and clinical applications.

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Hutchinson-Gilford progeria syndrome: Rejuvenating old drugs to fight accelerated ageing

Cited by 25 publications

References 115 publications

Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome

Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome

Development of a new drug for progeria syndrome; Past, Present and Future

Rapid and robust derivation of mesenchymal stem cells from human pluripotent stem cells via temporal induction of neuralized ectoderm

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